Nicotine reward is an integral part of the addictive nature of nicotine, however, smoking and relapse to smoking are often motivated by the desire to alleviate negative affect and deficits in cognitive performance. Moreover, nicotine abstinence symptoms that promote smoking relapse are most evident in the first few days after quitting, suggesting this as a critical period to investigate neural mechanisms that may contribute to smoking relapse. To date, the underlying circuitry and mechanism(s) associated with alterations in emotional processing and learning and memory following nicotine deprivation have not been elucidated. Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. In particular, the mouse is a tractable model that allows for dissection of these mechanisms at a molecular and genetic level not afforded by human studies. Therefore, the overall goal of this project is to characterize novel phenotypes in mice to determine the effects of the early period of nicotine deprivation. Specifically, in Aim 1 we will determine the effects of nicotine deprivation on brain stimulation reward (BSR) and contextual learning and working memory. We hypothesize that chronic nicotine administration alters neural processes underlying affect and learning and memory such that when chronic exposure ceases, anhedonia and deficits in learning and memory will emerge. In order to increase our ability to develop novel therapeutic approaches to treat nicotine dependence, it is important to validate the use of our preclinical models and behavioral phenotypes with clinically effective medications. Therefore, in aim 2 we will evaluate the effects of systemic administration of varenicline (Chantix) on brain stimulation reward (BSR) and contextual learning and working memory following nicotine deprivation. As smokers often report stress relief as a motivating factor contributing to continued smoking behavior, we will investigate a role for stress factors (CRF) during the period of early nicotine deprivation. Thus, in aim 3, we will delineate the molecular mechanisms associated with nicotine deprivation through investigations of CRF by evaluating CRF receptor signaling mechanisms and a downstream target of this signaling cascade, CREB (cAMP response element binding protein). Together these studies will provide insights into the molecular mechanisms underlying nicotine deprivation. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.